A. Field of the Invention
The present invention relates generally to the field of cancer therapy. More particularly, it concerns the use of benzimidazoles to elicit cell death in tumor cells and to inhibit angiogenesis. In addition, benzimidazoles may be used as treatments for other hyperproliferative diseases, including rheumatoid arthritis, inflammatory bowel disease, restenosis etc.
B. Description of Related Art
1. Cancer and p53
Normal tissue homeostasis is achieved by an intricate balance between the rate of cell proliferation and the rate of cell death. Disruption of this balance is thought to be a major deleterious event in the development of cancer. The inhibition of apoptosis (programmed cell death) has been linked to this disruptive event. The effects of such defects are catastrophic, causing over half a million deaths per annum in the United States alone.
It is well recognized that the expression of a tumor suppressor gene frequently inhibits cell growth and often induces apoptosis in a tumor cell. The p53 gene is a well known example of such a tumor suppressor gene (Monthenarh, 1992). There is now considerable evidence linking mutations of p53 and other tumor suppressor genes in the oncogenesis of many human cancers. There are numerous reports demonstrating that the growth of, for example, colon, glioblastoma, breast cancer, osteosarcoma and lung tumor cells can be suppressed by the expression of wild-type tumor suppressor genes.
For example, the introduction of wild-type p53 to a wide variety of p53-mutated tumor cells is sufficient to suppress of the malignant phenotype. These observations demonstrate that a high level of expression of wild-type p53 is a desirable course for the treatment of oncogenic malignancy.
As the half-life of p53 is very short, ranging between 15 and 20 minutes, it has proven difficult to increase the intracellular levels of p53 using conventional transfection strategies. The microcellular environment of these cells is such that overexpression of wild-type p53 protein, when achieved, is counteracted by rapid degradation. Hence, delivery of wild-type p53 into cancer cells using conventional viral vectors as a way of reducing tumor growth is at best inefficient.
The limitations in increasing the expression of exogenous p53 using conventional transfection strategies is exemplary of the constraints on sustained expression of other exogenous tumor suppressor genes. Therefore, there is a clear need for approaches to sustain induction or increase in tumor suppressor gene expression in cancer cells to mediate apoptosis in such cancer cells.
2. Angiogenesis
Angiogenesis, the development of new capillaries from preexisting blood vessels, plays a critical role in a variety of physiological processes and pathological conditions, including embryonic development, wound healing, tumor growth, metastasis, and various inflammatory disorders (Folkman, 1995a). It is now well documented that angiogenesis is required for metastasis and growth of solid tumors beyond a few cubic millimeters in size (Folkman, 1972; 1995b). Indeed, many research teams are exploring the therapeutic potential of such angiogenesis inhibitors as angiostatin, an ˜38-40-kDa fragment of plasminogen, endostatin (an ˜18-kDa fragment of collagen XVIII), transforming growth factor, thrombospondin-1, fumagillin, 2-methoxyestradiol, and thalidomide. This continues to be a promising area of cancer research.